Manganese carboxylates and the process of making them



,lethargic. encephalitis,

i citric, tartaric, mucic, :cinic, glycolic, a-aminobutyric, a-aminocaproic,

ter five time vvtle.

Patented Jan. 1, 1935 f' MANGANE'SE CARBOX YLATES Ann THE" ROC SS OF MAKINGEHEM/ 1 No DrawingI J Application April 3,..1933Qflfl.

My invention relates to manganese compounds suitable forfthe treatment of'infectiousdiseases such as staphylococcus infections, influenza, and

as by intramuscular "administrati'ons, Thexobject of this invention isa process of I forming water soluble manganese salts-of organic acidsof low toxicity, including the following acids: 'gluconic, galactonic, su'c-' aspartic, .glutamic; and acetyl glutamic sand the compounds formed thereby. j

.One illustrative procedure that has been found satisfactory is as follows: One hundred twelve grams of crystalline tetrahydrate oi manganous sulphate-are dissolved in 1500 cc. of water at roomftempeiiatu're. With rapid stirring 165 cc. of exactly six times normal sodium hydroxide were added. The strength of the hydroxide should be determined by titration, and. the amount added should be slightly less than the chemical equivalent of sulphatepresent. The stirring should be vigorous and result ina finely divided precipitate of maganous hydroxide.

This precipitate is washed with distilledwaby decantation, keeping the vessel covered while the precipitate is allowed to set- It is then filtered through a' suction filter, as rapidly as possible, and washed free from" sulphates. The precipitate is now stirred rapidly intoa suspension of 157 grams of glutamic acid in 500 cc. of Water at 90-100 C. During the ad.- dition and while thestirring is taking place, the temperature is raised rapidly 'to boiling. As soon as the addition is completed, the mass is filtered hot and the clear filtrate is concentrated under a reduced pressure of about 50 mm. to a syrupy consistency with a volume of about 200 cc. 3 While stirring this syrup with a clean spatula, 500 cc. of 95% ethyl alcohol are added, and the precipitated gummy mass is worked thoroughly until the consistency of the mass becomes crispy. This working ordinarily takes about ten minutes. The alcohol is thendecanted and a "new 300 cc. portion of alcohol is stirred in and then decanted, and two more 300 cc. portions are added successively and decanted, making a total of four successive treatments with 95% ethyl alcohol.

Finally the mass is washed with 400 cc. of absolute ethyl alcohol and the washings decanted. The mass is now dried in an oven as follows:

' alysis has given with 0.25

115 C. for twelve hours. I The resulting material is pulverized andagain- .dinarilytakesabout ten hours.

In one actual iexperiment .the :yield was a 148 grams, or:92% 'oflthe full theoretical amount. .Analysis of theproduct corresponds to a com- 1 formula -(C5HsO4N) zMni' :Q'uanti-' tative analysis of the product gave 15.70% .manganese and 8.11%24nitrogen against theoretical amounts of 15.82 manganese and 8.07% nitropound of the :gen. 3

An alternative procedure that is oprati'vebut the solution of. acid 100 C. for four days. In' this manner a glassy material" can be obtained which may be pulverized to powderand constant weight.

mula (C5H8OiN)'zMn.2H2O, and quantitative angen 7.41% v 14.33% for manganese and 7.31% for nitrogen. This compound is also suitable'for treatments but the anhydrous compound first described is preferred becauseit is notas hyg oscopic and has not safari-yielded quite assatisfactory-fre- :s'ults is to prepare :manganoushydroxide asxi-n the preceding example,- and after. evaporating manganous glutamate to a syrupy consistency, place 'the'same in an oven at dried again at 100 C(to This compound analyzes to be the dihydrate of the acid salt, with the for-,- I

25. manganese 14.30% and nitro f against theoretical percentages of 'canbe pulverized andha'ndled with greater ease.

I EachofXthe compounds obtained as above describe'djis very soluble in water and insoluble I in ethyl falcohol or ether. Aqueous solutions-give a very slightly acid reaction, and the pH of a 1% solution is 6.1. for one hour 'does not seem to deposit any film of the metallic oxidawhereas most manganese salts of forganic acids do deposit a film under such conditions. The addition of excess alkali, givesa precipitate of manganous hydroxide.

Heating to boiling For the purpose of injecting the aqueous solution of the compound intramuscularly to hu-,. i

man beings, we'flnd a 1% best method of administration. For most acute cases two injections of one cc. each in adults at intervals up to four days are suflicient. No

more than three injections should be given.

I am aware of the availability of manganese butyrate for similar intramuscular injection. I

solution of the salt) of phenolor meta-cresol 'tobe the" butyrate to be 37 mg. 01'

' um fatal dose for the acid glutamate prepared as described above is 62 mg. of manganese per kilogram of animal. From these results I conclude that the acid glutamate is about onehalf as toxic as the manganese butyrate. The administration of thebutyrate is also known to be painful.

the normal compound is insoluble in water;

glycerol, glycol, ethyl alcohol} or the usual organic solvents. It is not suitable for therapeutic purposes due to its insolubility. This has been confirmed by the fact that injections of a suspension in animals produced infiltrates at the .point of injection and had noapparent curative effect.

.The acid salt of mimic acid. could not be prepared by the usual methods, but procedure according to themethods outlined hereinabove is successfulin producing it.

.The dehydrated salt resulting from drying at 125 C. dissolves in water with ease, and the solution is identical with that obtained from the di-hydrate.

I have also prepared similar.water-soluble salts ofjthe other organic acids hereinabove mentioned other than butyric acid, and find them suitable for. therapeutic uses..

. Without further elaboration, will sofully explain the foregoing my invention that others 'may, by applying knowledge. current at the time of such application, readily adapt the same for use under various conditions of service.

I claim: 1

1. A process for making manganese glutamate suitable for pharmaceutical and therapeutic use and free from impurities detrimental to such use, which consists of treating a saturated solution of glutamic acid with finely divided manganous hydroxide at -100 C. and rapidly filtering, concentrating by evaporation under reduced pressure and precipitating by alcohol substantially as described.

' 2. A soluble manganese glutamate having 14.3% of manganeseand 7.4% of nitrogen.

3. A soluble manganese glutamate with 15.70% of manganese and 8.11% of nitrogen.

4. An acid manganese glutamate having one atom of manganese to two molecules of glutamic acid.

5. A water-soluble salt of manganese and glutamic acid.

6. A water. soluble salt of manganese and an acid selected from a group consisting of glycolic, a-aminobutyric, a-aminocaproic, aspartic, glutamic, and acetyl-glutamic acids. l

7. A process for making a Water-soluble salt of manganese and glutamic acid, which includes the step of reacting manganous hydoxide with glutamic acid in the proportions of the acid salt and at a temperature above that at which 1 the insoluble normal salt tends to form.

8. A process for making a water-soluble salt ,of manganese and glutamic acid, which includes the step of reacting manganous hydroxide with glutamic acid in aqueous solution.

I NICHOLAS D. CHERONIS. 

